RESUMO
Podocyte injury is the hallmark of proteinuric glomerular diseases. Notch3 is neo-activated simultaneously in damaged podocytes and podocyte's progenitor cells of FSGS, indicating a unique role of Notch3. We previously showed that activation of cAMP-PKA pathway alleviated podocyte injury possibly via inhibiting Notch3 expression. However, the mechanisms are unknown. In the present study, Notch3 signaling was significantly activated in ADR-induced podocytes in vitro and in PAN nephrosis rats and patients with idiopathic FSGS in vivo, concomitantly with podocyte dedifferentiation. In cultured podocytes, pCPT-cAMP, a selective cAMP-PKA activator, dramatically blocked ADR-induced activation of Notch3 signaling as well as inhibition of cAMP-PKA pathway, thus alleviating the decreased cell viability and podocyte dedifferentiation. Bioinformatics analysis revealed EP300/CBP, a transcriptional co-activator, as a central hub for the crosstalk between these two signaling pathways. Additionally, CREB/KLF15 in cAMP-PKA pathway competed with RBP-J the major transcriptional factor of Notch3 signaling for binding to EP300/CBP. EP300/CBP siRNA significantly inhibited these two signaling transduction pathways and disrupted the interactions between the above major transcriptional factors. These data indicate a crucial role of EP300/CBP in regulating the crosstalk between cAMP-PKA pathway and Notch3 signaling and modulating the phenotypic change of podocytes, and enrich the reno-protective mechanisms of cAMP-PKA pathway.
Assuntos
Desdiferenciação Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Proteína p300 Associada a E1A/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Fragmentos de Peptídeos/metabolismo , Podócitos/patologia , Receptor Notch3/metabolismo , Sialoglicoproteínas/metabolismo , Adulto , Animais , Apoptose , Biomarcadores/metabolismo , Proliferação de Células , Células Cultivadas , Proteína p300 Associada a E1A/genética , Feminino , Regulação da Expressão Gênica , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/metabolismo , Humanos , Masculino , Camundongos , Fragmentos de Peptídeos/genética , Podócitos/metabolismo , Prognóstico , Ratos , Ratos Sprague-Dawley , Receptor Notch3/genética , Sialoglicoproteínas/genéticaRESUMO
Cell replacement therapy is an area of increasing interest for treating Parkinson's disease (PD). However, to become a clinically practical option for PD patients, it must first overcome significant barriers, including establishment of safe and standardized surgical procedures, determination of appropriate perioperative medication regimens, demonstration of long-term graft survival and incorporation, and standardized, clinically meaningful follow-up measures. In this review, we will describe the current status of cell therapy for PD with special attention to these critical requirements, to define guideposts on the road to bring the benefit of this therapy to the Parkinson's clinic.